Prediction of Degradation Profiles for Various Sartans under Solvent-Free Mechanochemical Conditions.

For the approval of a drug, the stability data must be submitted to regulatory authorities. Such analyses are often time-consuming and cost-intensive. Forced degradation studies are mainly carried out under harsh conditions in the dissolved state, often leading to extraneous degradation profiles for a solid drug. Oxidative mechanochemical degradation offers the possibility of generating realistic degradation profiles. In this study, a sustainable mechanochemical procedure is presented for the degradation of five active pharmaceutical ingredients (APIs) from the sartan family: losartan potassium, irbesartan, valsartan, olmesartan medoxomil, and telmisartan. High-resolution mass spectrometry enabled the detection of impurities already present in untreated APIs and allowed the elucidation of degradation products. Significant degradation profiles could already be obtained after 15-60 min of ball milling time. Many of the identified degradation products are described in the literature and pharmacopoeias, emphasizing the significance of our results and the applicability of this approach to predict degradation profiles for drugs in the solid state.

Eco-friendly simultaneous estimation of atenolol and losartan potassium in spiked human plasma via synchronous fluorescence with sustainability assessment.

A green, sensitive, and fast spectrofluorimetric technique for the simultaneous determination of atenolol (ATN) and losartan potassium (LSR) was developed. The proposed technique relied on the implementation of a first derivative synchronous fluorescence spectroscopy for the determination of the investigated drugs simultaneously without pretreatment procedures. The synchronous fluorescence of both drugs was measured in methanol at Δλ of 100 nm, and the first derivative peak amplitudes (1D) were measured at 321 nm for ATN and 348 nm for LSR, each at the zero-crossing point of the other. The method was rectilinear over the concentration ranges of 100-1000 ng/mL and 50-500 ng/mL for ATN and LSR, respectively. The proposed technique was successfully applied for the determination of the studied drugs in their laboratory-prepared mixture and pharmaceutical formulations, demonstrating high mean recoveries of 100.54% for ATN and 100.62% for LSR, without interference from common excipients. The results were in good agreement with those obtained by the comparison method. Three recent greenness assessment tools, the Eco-Scale tool, the Green Analytical Procedure Index (GAPI) metric, and the Analytical GREEnness metric approach, were employed to affirm the greenness of the proposed method. The developed method was proven to be eco-friendly.

Development and validation of an analytical method for trace-level quantification of genotoxic nitrosamine impurities in losartan and hydrochlorothiazide fixed-dose combination tablets using ultra performance liquid chromatography triple quadrupole mass spectrometry.

RATIONALE: Since June 2018, globally large numbers of pharmaceuticals have been recalled due to the unexpected presence of nitrosamines. Beginning with the class of pharmaceuticals known as sartans, subsequent lines of inquiry included antidiabetic medicines, antihistamines, and antibiotics. A critical review of the U.S. Food and Drug Administration database reveals that the highest number of products recall due to the presence of unacceptable levels of nitrosamines were losartan potassium drug products and their coformulations with other drug substances. The problem can be mainly attributed to naively adopted approval revisions and the lack of sufficient current analytical technologies to detect those contaminants in time. In this work, we developed a specific, selective, accurate, precise, and robust ultra-performance liquid chromatography-triple quadrupole-mass spectrometry (UPLC-TQ-MS/MS) method for the estimation of eight genotoxic nitrosamine impurities in losartan and hydrochlorothiazide (HCTZ) tablets, which is the only fixed-dosage combination approved by the USFDA to treat hypertension. METHODS: All the nitrosamine impurities along with the drug substances were separated using an Agilent Pursuit XRs Ultra diphenyl column (150 × 2.0 mm, 2.8 µm) with mobile phase A (0.1% formic acid in water) and mobile phase B (0.1% formic acid in methanol) at a flow rate of 0.4 ml/min using the gradient elution program. The proposed method was validated per ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) Q2 (R1) guidelines to ensure the method is suitable for its intended purpose. RESULTS: Limit of detection and limit of quantification were obtained in the range of 0.25-0.5 ng/mL, which was very low compared to levels specified by the USFDA, European Medicines Agency (EMA), and other regulatory authorities that ensure the sensitivity of the method in its entire life cycle. CONCLUSIONS: The developed method can be incorporated into an official monograph and applied for routine quality control analysis of losartan and HCTZ fixed-dose combination tablets.

Microextraction by packed sorbent of N-nitrosamines from Losartan tablets using a high-throughput robot platform followed by liquid chromatography-tandem mass spectrometry.

The development of a fast, cost-effective, and efficient microextraction by packed sorbent setup was achieved by combining affordable laboratory-repackable devices of microextraction with a high-throughput cartesian robot. This setup was evaluated for the development of an analytical method to determine N-nitrosamines in losartan tablets. N-nitrosamines pose a significant concern in the pharmaceutical market due to their carcinogenic risk, necessitating their control and quantification in pharmaceutical products. The parameters influencing the performance of this sample preparation for N-nitrosamines were investigated through both univariate and multivariate experiments. Microextractions were performed using just 5.0 mg of carboxylic acid-modified polystyrene divinylbenzene copolymer as the extraction phase. Under the optimized conditions, the automated setup enabled the simultaneous treatment of six samples in less than 20 min, providing reliable analytical confidence for the proposed application. The analytical performance of the automated high-throughput microextraction by the packed sorbent method was evaluated using a matrix-matching calibration. Quantification was performed using ultra-high-performance liquid chromatography-tandem mass spectrometry with chemical ionization at atmospheric pressure. The method exhibited limits of detection as low as 50 ng/g, good linearity, and satisfactory intra-day (1.38-18.76) and inter-day (2.66-20.08) precision. Additionally, the method showed accuracy ranging from 80% to 136% for these impurities in pharmaceutical formulations.

Simultaneous quantification of losartan potassium and its active metabolite, EXP3174, in rabbit plasma by validated HPLC-PDA.

Herein, we report a novel, accurate and cost-effective validated analytical method for the quantification of losartan potassium and its active metabolite, EXP 3174, in rabbit plasma by reversed-phase high-performance liquid chromatography. Valsartan was used as an internal standard. The method was validated as per International Conference on Harmonization guidelines. The analytes were extracted in rabbit plasma using liquid-liquid extraction technique and analyzed at 247 nm after separation through a reverse-phase C18 column. The isocratic mobile phase used is a mixture of acetonitrile, water and glacial acetic acid in the ratio of 60:40:1 v/v/v maintained at pH 3.4. All calibration curves showed a good linear relationship (r > 0.995) within the test range. Precision was evaluated by intra- and interday tests with RSDs <1.91% and accuracy showed validated recoveries of 86.20-101.11%. Based on our results, the developed method features good quantification parameters and can serve as an effective quality control method for the standardization of drugs.

HPLC method transfer study for simultaneous determination of seven angiotensin II receptor blockers.

In this study, a sensitive high-performance liquid chromatography method was developed and validated for the simultaneous determination of seven angiotensin II receptor blockers, namely, hydrochlorothiazide, chlorthalidone, eprosartan mesylate, valsartan, losartan potassium, irbesartan, and candesartan cilexetil. Different chromatographic parameters were tested and fully optimized. Best chromatographic separation was accomplished on a reversed-phase octadecylsilyl column (250 × 4.6 mm id; 5 µm) under gradient elution using methanol/sodium phosphate monobasic buffer (0.01 M, pH 6.5) as mobile phase. The detection of target analytes was obtained at 254 nm. The pH of the buffer has been selected according to Marvin® sketch software. The proposed method was validated according to ICH guidelines and showed good precision (relative standard deviation < 1), good linearity (square of correlation coefficient ≥ 0.999), and high accuracy (between 98 and 102%) with detection limit and quantitation limit (40 and 160 ng/mL, respectively) for all the detected analytes.

First-derivative synchronous spectrofluorimetric method for estimation of losartan potassium and atorvastatin in their pure forms and in tablets.

Losartan potassium (LOS) and atorvastatin (ATR) are used in combination for long-term treatment of stroke and for treatment of hypertension with high-level cholesterol. Both drugs were simultaneously determined and validated using a novel, easy, fast, and economical first-derivative synchronous fluorescence spectroscopic method. Methanol was used as the solvent for both drugs at a Δλ 80 nm and with a scanning rate of 600 nm/min. Peaks were determined as at 288.1 nm and 263.6 nm for LOS and ATR, respectively. The proposed method was validated according to International Conference on Harmonization guidelines and, subsequently, the developed method was applicable to the analysis of the two compounds in their different formulations without interference from each other. Amplitude-concentration plots were rectilinear over the concentration ranges 1.0-10.0 µg/ml and 0.5-5.0 µg/ml for LOS and ATR, respectively. Detection limits were found to be 0.096 µg/ml and 0.030 µg/ml and quantitation limits were 0.291 µg/ml and 0.093 µg/ml for LOS and ATR, respectively. The proposed method was successfully applied to the analysis of both compounds in synthetic mixtures and in laboratory-prepared tablets. These results were in accordance with the results acquired using the comparison method, high-performance liquid chromatography.

SERS determination of the antihypertensive drugs prazosin and losartan by using silver nanoparticles coated with ß-cyclodextrin.

A surface-enhanced Raman scattering (SERS) method is described for the determination of prazosin (PRH) and losartan (LOS). Silver nanoparticles modified with ß-cyclodextrin (CD-S-Ag NPs) were prepared and serve as a sensitive SERS substrate. ß-CD is both a reductant for silver ions and a host molecule that binds the analytes which leads to strong SERS enhancement. The method has distinct features: (a) The linear response extends from 0.1 to 60 µM for PRH, and from 1.0 to 100 µM for LOS; (b) the respective limits of detection are as low as 15 nM and 0.92 µM; and (c) the specific SERS bands of PRH and LOS are located at 703 and 1298 cm-1 respectively. The method was successfully applied to the determination of PRH and LOS illegally added to healthcare products. The recovery of PRH and LOS from spiked samples ranges between 91.3 and 109.3%, and from 87.4 to 105.2%, respectively, both with relative standard deviation of <5%. Graphical abstractSchematic representation of a SERS method involving ß-CD-S-Ag nanoparticles for determination of prazosin and losartan via formation of an inclusion complex.

A nanocomposite prepared from a polypyrrole deep eutectic solvent and coated onto the inner surface of a steel capillary for electrochemically controlled microextraction of acidic drugs such as losartan.

The authors describe a new coating for use in electrochemically controlled in-tube solid phase microextraction (EC-IT-SPME). It consists of a nanocomposite that was prepared from polypyrrole and deep eutectic solvent (DES) by electrochemical deposition on the inner walls of a stainless steel capillary that serves as a working electrode. The hypertension drug losartan acts as an acidic model analyte. The extraction efficiency, mechanical stability, chemical stability and lifetime of the coating were investigated. It is found to be quite stable in relatively acidic and basic media and to be re-usable >450 times without decrease in extraction efficiency. Its extraction capability in comparison to the commercial polypyrrole coating is better by a factor of 1.5. The coated steel capillary was used as the anode (anion-exchanger), and a platinum electrode was used as the cathode. By passing a sample solution through the electrode, losartan can be extracted by applying a positive potential to the flow. In the next step, losartan is electrochemically desorbed and subjected to HPLC analysis with UV detection. Under optimal conditions, losartan can be quantified with limits of detection that range from 50 to 500 ng L-1 depending on the sample matrix. Response is linear in the 0.1-500 µg L-1 concentration range. The inter- and intra-assay precisions (RSDs; in %, for n = 3) are in the range from 2.4-4.6% and from 1.9-3.9%, respectively. Graphical abstract Schematic of the preparation of a nano-structured polypyrrole-deep eutectic solvent nanocomposite coating placed on the inner surface of a stainless steel capillary and used for electrochemically controlled in-tube solid phase microextraction of losartan from biological samples.

Spectroscopic and cytotoxic studies of losartan complexes.

Use of drug-metal complexes for the treatment of several human diseases has resulted in significant progress in the field of medicinal inorganic chemistry. The current study describes the synthesis and characterization of Cu (II) and Ni (II) complexes of Losartan, an antihypertensive drug. These complexes were evaluated for their cytotoxic activity against four human cancer cell lines; SNB-19, HCT-15, COLO-205 and KB-3-1. Spectroscopic characterization revealed that during complex formation, the metal was bound through the nitrogen atoms of the tetrazole moiety of the losartan molecule. The molecular formulas of copper ([Cu (LS) 2 Cl2].6H2O) and nickel ([Ni (LS) 2Cl2]. H2O) complexes were found to be in agreement with the analytical data obtained through elemental analysis. For both the complexes, metal to ligand ratios of 1:2 were calculated. As revealed by FTIR, UV-Visible, and 1H-NMR studies, both the complexes displayed octahedral geometries. Scanning electron microscopy (SEM) revealed marked changes in the morphology of the complexes, compared to the pure drug. From XRD studies, characteristic crystalline peaks of pure losartan were observed whereas no prominent peaks were observed for its complexes. Complexes were found to be inactive in the cytotoxic activity test performed using SNB-19, HCT-15, COLO-205 and KB-3-1 cell lines.

Unveiling intricate transformation pathways of emerging contaminants during wastewater treatment processes through simplified network analysis.

As the key stage for purifying wastewater, elimination of emerging contaminants (ECs) is found to be fairly low in wastewater treatment plants (WWTPs). However, less knowledge is obtained regarding the transformation pathways between various chemical structures of ECs under different treatment processes. This study unveiled the transformation pathways of ECs with different structures in 15 WWTPs distributed across China by simplified network analysis (SNA) we proposed. After treatment, the molecular weight of the whole component of wastewater decreased and the hydrophilicity increased. There are significant differences in the structure of eliminated, consistent and formed pollutants. Amino acids, peptides, and analogues (AAPAs) were detected most frequently and most removable. Benzenoids were refractory. Triazoles were often produced. The high-frequency reactions in different WWTPs were similar, (de)methylation and dehydration occurred most frequently. Different biological treatment processes performed similarly, while some advanced treatment processes differed, such as a significant increase of -13.976 (2HO reaction) paired mass distances (PMDs) in the chlorine alone process. Further, the common structural transformation was uncovered. 4 anti-hypertensive drugs, including irbesartan, valsartan, olmesartan, and losartan, were identified, along with 22 transformation products (TPs) of them. OH2 and H2O PMDs occurred most frequently and in 80.81 % of the parent-transformation product pairs, the intensity of the product was higher than parent in effluents, whose risk should be considered in future assessment activity. Together our results provide a macrography perspective on the transformation processes of ECs in WWTPs. In the future, selectively adopting wastewater treatment technology according to structures is conductive for eliminating recalcitrant ECs in WWTPs.

Resolution of overlapping spectra using chemometric manipulations of UV-spectrophotometric data for the determination of Atenolol, Losartan, and Hydrochlorothiazide in pharmaceutical dosage form.

Simultaneous determination of atenolol (ATN), losartan potassium (LOS), and hydrochlorothiazide (HCZ) in presence of HCZ impurity B was conducted by chemometric approaches and radial basis function network (RBFN) using UV-spectrophotometry without preliminary separation. Three chemometric models namely, classical least-squares (CLS), principal component regression (PCR), and partial least-squares (PLS) along with RBFN were utilized using the ternary mixtures of the three drugs. The multivariate calibrations were obtained by measuring the zero-order absorbance of the mixtures from 250 to 270 nm at the interval of 0.2 nm. The models were built covering the concentration range of (4.0 to 20.0), (3.8 to 20.2), and (0.9 to 50.1) µg mL-1 for ATN, LOS, and HCZ, respectively. The regression coefficient was calculated between the actual and predicted concentrations of the 3 drugs using CLS, PCR, PLS and RBFN. The accuracy of the developed models was evaluated using the root mean square error of prediction (RMSEP) giving satisfactory results. The proposed methods were simple, accurate, precise and were applied efficiently for the quantitation of the three components in laboratory-prepared mixtures, and in dosage form showing good recovery values. In addition, the obtained results were compared statistically with each other using ANOVA test showing non-significant difference between them.

A design of experiment based RP-HPLC method for the simultaneous estimation of antihypertensive drugs with greenness assessment.

The correlation between blood pressure (BP) and cardiovascular risk has a continuous, positive, and linear pattern. Lowering high BP decreases the risk associated with cardiovascular disease. Chlorthalidone (CHD) and Losartan potassium (LOS) combination is used to treat hypertension. The analytical community was concerned with minimizing or reducing the use of toxic chemicals and solvents. Therefore, the current study aimed to develop a rapid, sensitive, and cost-effective green RP-HPLC method to determine CHD and LOS simultaneously in a short analysis of time. Method optimization was performed by Central composite design (CCD), the flow rate and the change of time were chosen as factors. Effective separation was conducted on Zorbax SB-C18 (4.6 mm × 150 mm, 5 µm) column by gradient mobile phase comprising phosphate buffer and ethanol flowing at 0.859 ml/min, and the wavelength detected at 230 nm. As per ICH criteria, the technique was proven to be precise, accurate, and linear over the concentration range of 4.3-8.1 µg/ml for CHD and 35-65 µg/ml for LOS. Furthermore, the method's greenness was examined by three different metrics, confirming that less toxic effect on the environment. Hence, the optimized approach proves to be eco-friendly, simple, and robust for the concurrent evaluation of CHD and LOS in pharmaceutical formulations.

Targeted and untargeted screening for impurities in losartan tablets marketed in Germany by means of liquid chromatography/high resolution mass spectrometry.

Technical advances in the field of quality analysis allow an increasingly deeper look into the impurity profile of drugs. The ability to detect unexpected impurities in addition to known impurities ensures the supply of high-quality drugs and can prevent recalls due to the detection of harmful unexpected impurities, as has happened recently with the N-nitrosamine and azido impurities in losartan (LOS) drug products. In the present study, the LC-MS/HRMS approach described by Backer et al. was applied to an even more complex system, being the investigation of 35 LOS drug products and combination preparations purchased in 2018 and 2022 in German pharmacies. The film-coated tablets were analysed by means of four LC-MS/HRMS method variants. For the separation a Zorbax RR StableBond C18 column (3.0 ×100 mm, particle size of 3.5 µm, pore size of 80 Å), a gradient elution and for mass spectrometric detection a qTOF mass spectrometer with electrospray ionization in positive and negative mode was used. An information-dependent acquisition method was applied for the acquisition of high-resolution mass spectrometry data. The combination of an untargeted and a targeted screening approach revealed the finding of eight impurities in total. Beside the five LOS related compounds, LOS impurity F, J, K, L, M, and related compound D from amlodipine besilate, LOS azide and an unknown derivative thereof were detected. Identification and structure elucidation, respectively, were successfully performed using in silico fragmentation. Differences in the impurity profiles of drug products from 2018 and 2022 could be observed. This study shows that broad screening approaches like this are applicable to the analysis of drug products and can be an important enhancement of the quality assurance of medicinal products.

Drug Release and Stability Study of Innovated Losartan Potassium and Rosuvastatin Calcium Fixed-dose Combination Tablet.

BACKGROUND: Patient adherence to therapy and compliance is always a challenge for care providers in the management of chronic disorders with multiple medications. OBJECTIVE: Our study focused on formulating concurrently prescribed ARB (Angiotensin Receptor Blocker), i.e., losartan potassium, and a cholesterol-lowering statin derivative, i.e., rosuvastatin calcium, in a fixed-dose combination tablet. METHODS: The drugs were selected based on the presence of synergism and variation in solubility characteristics. Trial batches with fixed concentrations of both active pharmaceutical ingredients (APIs) and varying quantities of different excipients were prepared by dry granulation technique and subjected to different quality control tests for tablets. Batch F5 was selected on the basis of in-process quality control data for the development of a drug release protocol. Experimental conditions were optimized. Based on the sink condition, phosphate buffer (pH 6.8) was selected as the dissolution medium. Simultaneous determination of both APIs in samples collected at predetermined time intervals was carried out using the RP-HPLC technique with acetonitrile, methanol, and water (20:25:55 v/v/v) as mobile phase. RESULTS: Complete dissolution of both APIs in the FDC tablet was achieved in 45 min in 900 mL of the selected medium. The in vitro drug release protocol was validated for accuracy and precision without interference with sample analysis. CONCLUSION: In this study, a validated, accurate, and robust dissolution testing method was developed for the newly formulated FDC tablet.

Utility of 4-chloro-7-nitrobenzofurazan (NBD-CI) for the Spectrophotometric and spectrofluorometric determination of several antihistamine and antihypertensive drugs.

New, sensitive, and selective spectrophotometric and spectrofluorometric methods have been developed for determination of clemastine hydrogen fumarate (Clem), loratadine (Lor), losartan potassium (Los), and ramipril (Ram) in both pure form and pharmaceutical formulations using 4-chloro-7-nitrobenzofurazan (NBD-CI), which is a highly sensitive chromogenic and fluorogenic reagent. The relation between absorbance at 470, 467, 471, and 469 nm and the concentration was linear over the ranges 5-35, 10-100, 10-90, and 10-120 microg/mL for Clem, Lor, Los, and Ram, respectively. The complexation products were also measured spectrofluorometrically at the emission wavelength 535 nm for Clem, Lor, and Ram and at 538 nm for Los with excitation at 477 and 452 nm for Clem and Lor, respectively, and 460 nm for both Los and Ram. The fluorescence intensity was directly proportional to the drug concentration over the ranges 0.05-0.5, 5-20, 1-6, and 2-15 microg/mL for Clem, Lor, Los, and Ram, respectively. The methods were successfully applied for the determination of the studied drugs in pharmaceutical dosage forms with excellent recovery.

Determination of losartan potassium, quinapril hydrochloride and hydrochlorothiazide in pharmaceutical preparations using derivative spectrophotometry and chromatographic-densitometric method.

Two methods, spectrophotometric and chromatographic-densitometric ones, were developed for determination of losartan potassium, quinapril hydrochloride and hydrochlorothiazide in pharmaceutical preparations. Spectrophotometric method involved derivative spectrophotometry and zero order spectrophotometry. The measurements were carried out at lambda = 224.0 nm for quinapril, lambda = 261.0 nm for hydrochlorothiazide and lambda = 270.0 nm for losartan when the derivative spectrophotometry was applied and lambda = 317.0 nm when zero order spectrophotometry was applied for the determination of hydrochlorothiazide. In chromatographic-densitometric studies high performance thin layer chromatography (HPTLC) plates were used as stationary phase and a mixture of solvents n-butanol : acetic acid : water (15 : 5 : 1, v/v/v) as mobile phase. Under the established conditions good resolution of examined constituents was obtained. Retardation factor for quinapril hydrochloride was R(f) - 0.70, for losartan potassium R(f) - 0.85 and for hydrochlorothiazide R(f) - 0.78. The developed methods are characterized by high sensitivity and accuracy. For quantitative analysis, densitometric measurements were carried out at lambda = 218.0 nm for quinapril, lambda = 275.0 nm for hydrochlorothiazide and = 232.0 nm for losartan.

Sartan blood pressure regulators in classical and biofilm wastewater treatment - Concentrations and metabolism.

Sartans are a group of pharmaceuticals widely used to regulate blood pressure. Their concentration levels were monitored in 80 wastewater treatment plants (WWTP) in the Baltic Sea Region, reached from limit of detection up to 6 µg/L. The concentrations were significantly different in different countries, but consistent within the respective country. The degradation of sartans (losartan, valsartan, irbesartan) in moving bed biofilm reactors (MBBRs) that utilize biofilms grown on mobile carriers to treat wastewater was investigated for the first time, and compared with the degradation in a conventional activated sludge (CAS) treatment plant. The results showed the formation of six microbial transformation products (TPs) of losartan, four of valsartan, and four of irbesartan in biological wastewater treatment. Four of these metabolites have not been described in the literature before. Chemical structures were suggested and selected TPs were verified and quantified depending on availability of true standards. Valsartan acid was a common TP of losartan, valsartan, and irbesartan. Losartan and irbesartan also shared one TP: losartan/irbesartan TP335. Based on the mass balance analysis, losartan carboxylic acid is the main TP of losartan, and valsartan acid is the main TP of valsartan during the biotransformation process. For irbesartan, TP447 is likely to be the main TP, as its peak areas were two orders of magnitude higher than those of all the other detected TPs of this compound. The effects of adapting biofilms to different biological oxygen demand (BOD) loading on the degradation of sartans as well as the formation of their TPs were investigated. Compared to feeding a poor substrate (pure effluent wastewater from a CAS), feeding with richer substrate (1/3 raw and 2/3 effluent wastewater) promoted the metabolism of most compounds (co-metabolization). However, the addition of raw wastewater inhibited some metabolic pathways of other compounds, such as from losartan/irbesartan to TP335 (competitive inhibition). The formation of irbesartan TP447 did not change with or without raw wastewater. Finally, the sartans and their TPs were investigated in a full-scale CAS wastewater treatment plant (WWTP). The removal of losartan, valsartan, and irbesartan ranged from 3.0 % to 72% and some of the transformation products (TPs) from human metabolism were also removed in the WWTP. However, some of the sartan TPs, i.e., valsartan acid, losartan carboxylic acid, irbesartan TP443 and losartan TP453, were formed in the WWTP. Relative high amounts of especially losartan carboxylic acid, which was detected with concentrations up to 2.27 µg/L were found in the effluent.

From data to reliable conclusions: Identification and comparison of persistent micropollutants and transformation products in 37 wastewater samples by non-target screening prioritization.

In this study, micropollutants in wastewater effluents were prioritized by monitoring the composition of influent and effluent wastewater by liquid chromatography - high-resolution mass spectrometry (LCHRMS) non-target screening (NTS) analysis. The study shows how important data pre-processing and filtering of raw data is to produce reliable NTS data for comparison of compounds between many samples (37 wastewater samples) analyzed at different times. Triplicate injections were critical for reducing the number of false-positive detections. Intensity drift corrections within and between batches analyzed months apart made peak intensities comparable across samples. Adjustment of the feature detection threshold was shown to be important, due to large intensity variations for low abundance compounds across batches. When the threshold correction cut-offs, or the filtering of relevant compounds by the occurrence frequency, were too stringent, a high number of false positive transformation products (TPs) were reported. We also showed that matrix effect correction by internal standards can over- or under-correct the intensity for unknown compounds, thus the TIC matrix effect correction was shown as an additional tool for a retention time dependent matrix effect correction. After these preprocessing and filtering steps, we identified 78 prioritized compounds, of which 36 were persistent compounds, defined as compounds with a reduction in peak intensity between influent and effluent wastewater <50%, and 13 compounds were defined as TPs because they occurred solely in the effluent samples. Some examples of persistent compounds are 1,3-diphenylguanidine, amisulpride and the human metabolites from losartan, verapamil and methadone. To our knowledge, nine of the identified TPs have not been previously described in effluent wastewater. The TPs were derived from metoprolol, fexofenadine, DEET and losartan. The screening of all identified compounds in effluent samples from eight wastewater treatment plants (WWTPs) showed that potential drugs of abuse, anti-psychotic and anti-depressant drugs were predominant in the capital city region, whereas the anti-epileptic agents and agricultural pesticides were dominant in more rural areas.

Effect of losartan potassium, metformin hydrochloride, and simvastatin on in vitro bioaccessibility of Cu, Fe, Mn, and Zn in oat flour from Brazil.

BACKGROUND: The simultaneous administration of drugs with food can compromise the bioaccessibility and absorption of nutrients. The objective of this study was to evaluate the influence of the use of losartan potassium (LP), metformin hydrochloride (MH), and simvastatin (S) on the in vitro bioaccessibility of micronutrients (Cu, Fe, Mn, and Zn) in oat flour from Bahia, Brazil. METHODS: The experimental procedure consisted of the in vitro extraction of the bioaccessible fraction of Cu, Fe, Mn, and Zn in oat flour-with and without LP (50 mg), MH (500 mg), and S (20 mg)-using the unified bioaccessibility method (UBM), simulating the conditions of the gastrointestinal tract. For decomposition of the samples (oat flour and residue), a digester block with a closed system was used. To determine the total content (flour and residual fraction) and bioaccessible micronutrients, inductively coupled plasma optical emission spectrometry (ICP OES) was used. RESULTS: The bioaccessible contents (µg g-1) without the addition of drugs were: Cu 5.86 ± 0.21, Fe 32.80 ± 1.32, Mn 87.90 ± 1.90, and Zn 30.33 ± 2.05, with bioaccessibility ranging from 31.5 % for Fe to 99 % for Mn. The in vitro extraction method was validated by mass balance with recovery values from 89.78 % for Cu to 101.94 % for Mn. The range of bioaccessible contents (µg g-1) were: Cu (<4.14), Fe (32.10 ± 0.20-54.10 ± 2.03), Mn (81.40 ± 0.93-93.22 ± 0.80), and Zn (<10.80-29.11 ± 2.20). The estimation of the bioaccessibility of Cu, Mn, and Zn in oat flour were compromised in the presence of LP, MH, and S (p < 0.05). CONCLUSION: Chemical interactions can occur between drugs and micronutrients. Taken together, our results highlight that LP, MH, and S can interfere with the bioaccessibility of Cu, Fe, Mn, and Zn in oat flour in patients who use these drugs, suggesting its rational use in further investigations.